Extracellular Matrix Structure and Interaction with Immune Cells in Adult Astrocytic Tumors.

The extracellular matrix (ECM) is a dynamic set of molecules produced by the cellular component of normal and pathological tissues of the embryo and adult. ECM acts as critical regulator in various biological processes such as differentiation, cell proliferation, angiogenesis, and immune control. The most frequent primary brain tumors are gliomas and by far the majority are adult astrocytic tumors (AATs). The prognosis for patients with these neoplasms is poor and the treatments modestly improves survival. In the literature, there is a fair number of studies concerning the composition of the ECM in AATs, while the number of studies relating the composition of the ECM with the immune regulation is smaller. Circulating ECM proteins have emerged as a promising biomarker that reflect the general immune landscape of tumor microenvironment and may represent a useful tool in assessing disease activity. Given the importance it can have for therapeutic and prognostic purposes, the aim of our study is to summarize the biological properties of ECM components and their effects on the tumor microenvironment and to provide an overview of the interactions between major ECM proteins and immune cells in AATs. As the field of immunotherapy in glioma is quickly expanding, we retain that current data together with future studies on ECM organization and functions in glioma will provide important insights into the tuning of immunotherapeutic approaches.

Progressive supranuclear palsy with marked ventricular dilatation mimicking normal pressure hydrocephalus.

BACKGROUND: Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients. METHODS: One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) > 0.32 associated with callosal angle (CA) < 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients. RESULTS: Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement. DISCUSSION: Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.

Magnetic Resonance Imaging Biomarkers Distinguish Normal Pressure Hydrocephalus From Progressive Supranuclear Palsy.

BACKGROUND: Idiopathic normal pressure hydrocephalus and PSP share several clinical and radiological features, making differential diagnosis, at times, challenging. OBJECTIVES: To differentiate idiopathic normal pressure hydrocephalus from PSP using MR volumetric and linear measurements. METHODS: Twenty-seven idiopathic normal pressure hydrocephalus patients, 103 probable PSP patients, and 43 control subjects were consecutively enrolled. Automated ventricular volumetry was performed using Freesurfer 6 on MR T1 -weighted images. Linear measurements, such as callosal angle and a new measure, termed MR Hydrocephalic Index, were calculated on MR T1 -weighted images. Receiver operating characteristic analyses were used for differentiating between patient groups. Generalizability and reproducibility of the results were validated, dividing each participant group in two cohorts used as training and testing subsets. RESULTS: Ventricular volumes and linear measurements (callosal angle and Magnetic Resonance Hydrocephalic Index) revealed greater ventricular enlargement in patients with idiopathic normal pressure hydrocephalus than in PSP patients and controls. PSP patients had ventricular volume larger than controls. Automated ventricular volumetry and Magnetic Resonance Hydrocephalic Index were the most accurate measures (98.5%) in differentiating patients with idiopathic normal pressure hydrocephalus from PSP patients, whereas callosal angle misclassified several PSP patients and showed low positive predictive value (70.0%) in differentiating between these two diseases. All measurements accurately differentiated idiopathic normal pressure hydrocephalus patients from controls. Accuracy values obtained in the training set (automated ventricular volumetry, 98.4%; Magnetic Resonance Hydrocephalic Index, 98.4%; callosal angle, 87.5%) were confirmed in the testing set. CONCLUSIONS: Our study demonstrates that AVV and Magnetic Resonance Hydrocephalic Index were the most accurate measures for differentiation between idiopathic normal pressure hydrocephalus and PSP patients. Magnetic Resonance Hydrocephalic Index is easy to measure and can be used in clinical practice to prevent misdiagnosis and ineffective shunt procedures in idiopathic normal pressure hydrocephalus mimics. © 2020 International Parkinson and Movement Disorder Society.

UbcH10 a Major Actor in Cancerogenesis and a Potential Tool for Diagnosis and Therapy.

Malignant transformation is a multistep process in which several molecular entities become dysregulated and result in dysfunction in the regulation of cell proliferation. In past years, scientists have gradually dissected the pathways involved in the regulation of the cell cycle. The mitotic ubiquitin-conjugating enzymes UbcH10, has been extensively studied since its cloning and characterization and it has been identified as a constantly overexpressed factor in many types of cancer. In this paper, we have reviewed the literature about UbcH10 in human cancer, pointing out the association between its overexpression and exacerbation of cancer phenotype. Moreover, many recalled studied demonstrated how immunohistochemistry or RT-PCR analysis can distinguish normal tissues and benign lesions from malignant neoplasms. In other experimental studies, many of the consequences of UbcH10 overexpression, such as increased proliferation, metastasizing, cancer progression and resistance to anticancer drugs are reversed through gene silencing techniques. In recent years, many authors have defined UbcH10 evaluation in cancer patients as a useful tool for diagnosis and therapy. This opinion is shared by the authors who advertise how it would be useful to start using in clinical practice the notions acquired about this important moleculein the carcinogenesis of many human malignancies.

Microenvironment Molecular Profile Combining Glycation Adducts and Cytokines Patterns on Secretome of Short-term Blood-derived Cultures during Tumour Progression.

Cancer cells are known to secrete many bioactive factors acting both with paracrine and autocrine mechanisms by which they condition the surrounding microenvironment. At the same time, the intracytoplasmic metabolic activities microenvironment influences the profile of this secretion. It is well known that cancer cells exhibit prevalent glycolytic metabolism and a more oxidative atmosphere compared to their healthy counterparts; this metabolic phenotype promotes glycate adducts formation and secretion. Considering the exacerbation of metabolic changes during the cancer progression, it is suggestive to explore the potential correlation between the increasing rate of glycan adducts and the specific pattern of secreted cytokines in different phases of cancer disease. We analyzed the secretomes of blood-derived cancer cell cultures from cancer patients and healthy subjects. The relative glycate adducts content in cancer secretomes was higher in comparison to that of healthy samples. Moreover, the stratification based on different phases of cancer disease correlated with a specific cytokines panel. The results obtained open a new perspective of observation of the intricate relationship between metabolome and inflammation in cancer. By using the analysis of secretome combined with a standardized protocol of liquid biopsy, it would be possible to identify specific profiles of molecular markers useful to arrange alternative and personalized medicine strategies.

MiRNA expression profiling in human gliomas: upregulated miR-363 increases cell survival and proliferation.

The role of microRNAs (miRNAs) in glioma biology is increasingly recognized. To investigate the regulatory mechanisms governing the malignant signature of gliomas with different grades of malignancy, we analyzed miRNA expression profiles in human grade I-IV tumor samples and primary glioma cell cultures. Multiplex real-time PCR was used to profile miRNA expression in a set of World Health Organization (WHO) grade I (pilocytic astrocytoma), II (diffuse fibrillary astrocytoma), and IV (glioblastoma multiforme) astrocytic tumors and primary glioma cell cultures. Primary glioma cell cultures were used to evaluate the effect of transfection of specific miRNAs and miRNA inhibitors. miRNA microarray showed that a set of miRNAs was consistently upregulated in all glioma samples. miR-363 was upregulated in all tumor specimens and cell lines, and its expression correlated with tumor grading. The transfection of glioma cells with the specific inhibitor of miR-363 increased the expression level of tumor suppressor growth-associated protein 43 (GAP-43). Transfection of miR-363 induced cell survival, while inhibition of miR-363 significantly reduced glioma cell viability. Furthermore, miRNA-363 inhibition induced the downregulation of AKT, cyclin-D1, matrix metalloproteinase (MMP)-2, MMP-9, and Bcl-2 and upregulation of caspase 3. Together, these data suggest that the upregulation of miR-363 may play a role in malignant glioma signature.

Anesthetic techniques and cancer recurrence after surgery.

Many of the most common anesthetics are used in surgical oncology, yet effects on cancer cells are still not known. Anesthesia technique could differentially affect cancer recurrence in oncologic patients undergoing surgery, due to immunosuppression, stimulation of angiogenesis, and dissemination of residual cancer cells. Data support the use of intravenous anesthetics, such as propofol anesthesia, thanks to antitumoral protective effects inhibiting cyclooxygenase 2 and prostaglandins E2 in cancer cells, and stimulation of immunity response; a restriction in the use of volatile anesthetics; restriction in the use of opioids as they suppress humoral and cellular immunity, and their chronic use favors angiogenesis and development of metastases; use of locoregional anesthesia compared with general anesthesia, as locoregional appears to reduce cancer recurrence after surgery. However, these findings must be interpreted cautiously as there is no evidence that simple changes in the practice of anesthesia can have a positive impact on postsurgical survival of cancer patients.

Anatomo-physiological basis and applied techniques of electrical neuromodulation in chronic pain.

Chronic pain, a complex and debilitating condition, poses a significant challenge to both patients and healthcare providers worldwide. Conventional pharmacological interventions often prove inadequate in delivering satisfactory relief while carrying the risks of addiction and adverse reactions. In recent years, electric neuromodulation emerged as a promising alternative in chronic pain management. This method entails the precise administration of electrical stimulation to specific nerves or regions within the central nervous system to regulate pain signals. Through mechanisms that include the alteration of neural activity and the release of endogenous pain-relieving substances, electric neuromodulation can effectively alleviate pain and improve patients' quality of life. Several modalities of electric neuromodulation, with a different grade of invasiveness, provide tailored strategies to tackle various forms and origins of chronic pain. Through an exploration of the anatomical and physiological pathways of chronic pain, encompassing neurotransmitter involvement, this narrative review offers insights into electrical therapies' mechanisms of action, clinical utility, and future perspectives in chronic pain management.

Intraoperative Neurophysiological Monitoring in Neurosurgery.

Intraoperative neurophysiological monitoring (IONM) is a crucial advancement in neurosurgery, enhancing procedural safety and precision. This technique involves continuous real-time assessment of neurophysiological signals, aiding surgeons in timely interventions to protect neural structures. In addition to inherent limitations, IONM necessitates a detailed anesthetic plan for accurate signal recording. Given the growing importance of IONM in neurosurgery, we conducted a narrative review including the most relevant studies about the modalities and their application in different fields of neurosurgery. In particular, this review provides insights for all physicians and healthcare professionals unfamiliar with IONM, elucidating commonly used techniques in neurosurgery. In particular, it discusses the roles of IONM in various neurosurgical settings such as tumoral brain resection, neurovascular surgery, epilepsy surgery, spinal surgery, and peripheral nerve surgery. Furthermore, it offers an overview of the anesthesiologic strategies and limitations of techniques essential for the effective implementation of IONM.

Changes in cerebral cortex activity during a simple motor task after MRgFUS treatment in patients affected by essential tremor and Parkinson's disease: a pilot study using functional NIRS.

Objective.Magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) is a non-invasive thermal ablation method that involves high-intensity focused ultrasound surgery (FUS) and Magnetic Resonance Imaging for anatomical imaging and real-time thermal mapping. This technique is widely employed for the treatment of patients affected by essential tremor (ET) and Parkinson's disease (PD). In the current study, functional near-infrared spectroscopy (fNIRS) was used to highlight hemodynamics changes in cerebral cortex activity, during a simple hand motor task, i.e. unimanual left and right finger-tapping, in ET and PD patients.Approach.All patients were evaluated before, one week and one month after MRgFUS treatment.Main results.fNIRS revealed cerebral hemodynamic changes one week and one month after MRgFUS treatment, especially in the ET group, that showed a significant clinical improvement in tremor clinical scores.Significance.To our knowledge, our study is the first that showed the use of fNIRS system to measure the cortical activity changes following unilateral ventral intermediate nucleus thalamotomy after MRgFUS treatment. Our findings showed that therapeutic MRgFUS promoted the remodeling of neuronal networks and changes in cortical activity in association with symptomatic improvements.

Long-term follow-up of ruptured intracranial aneurysms treated by microsurgical wrapping with autologous muscle.

The purpose of this study is to describe our series of nine unclippable and uncoilable ruptured aneurysms in eight patients treated by microsurgical wrapping with autologous muscle. Records were retrospectively reviewed for rebleeding rate, morbidity and mortality, changes in size or the aneurysm's configurations, and inflammatory reaction. We conducted a Medline search in the post-microsurgical era, excluding patients in whom wrapping was part of the aneurysm treatment in combination with clipping or coiling. The surgically related morbidity was 12.5%. Global mortality rate was 25% due to vasospasm (one case) and rebleeding (one case). Six patients are still alive. Rebleeding rate was 14.3% within 6 months; then, it was zero. Glasgow outcome scale (GOS) score at discharge was 1 and 4 in one patient, respectively, and 5 in the remaining six. Mean clinical follow-up was 126 months. GOS at last follow-up was 4 and 5 in 50% of patients, respectively. Mean mRS score was 0.8 at 2 months, and 2.4 at 12 months. Follow-up MR demonstrated persistence of the aneurysm's sac, without changes in size and configuration. Patients did not describe or exhibit symptoms attributable to complications inherent to the use of muscle. Microsurgical muscle-wrapping of ruptured intracranial aneurysm is safe, is associated with a low rate of acute and delayed postoperative complications and rebleeding, and could be a valid alternative for unclippable and non-amenable to endovascular procedure ruptured aneurysms.

Design and Experimental Validation of a 3D-Printed Embedded-Sensing Continuum Robot for Neurosurgery.

A minimally-invasive manipulator characterized by hyper-redundant kinematics and embedded sensing modules is presented in this work. The bending angles (tilt and pan) of the robot tip are controlled through tendon-driven actuation; the transmission of the actuation forces to the tip is based on a Bowden-cable solution integrating some channels for optical fibers. The viability of the real-time measurement of the feedback control variables, through optoelectronic acquisition, is evaluated for automated bending of the flexible endoscope and trajectory tracking of the tip angles. Indeed, unlike conventional catheters and cannulae adopted in neurosurgery, the proposed robot can extend the actuation and control of snake-like kinematic chains with embedded sensing solutions, enabling real-time measurement, robust and accurate control of curvature, and tip bending of continuum robots for the manipulation of cannulae and microsurgical instruments in neurosurgical procedures. A prototype of the manipulator with a length of 43 mm and a diameter of 5.5 mm has been realized via 3D printing. Moreover, a multiple regression model has been estimated through a novel experimental setup to predict the tip angles from measured outputs of the optoelectronic modules. The sensing and control performance has also been evaluated during tasks involving tip rotations.

A novel 3D anatomical visualization system to avoid injuries of nerves in retrosigmoid approach.

The retro-sigmoid approach (RA), widely used during different neurosurgical procedures, is burdened by the risk of injuries of the nerves that cross that region contributing to possible postoperative complications. By using, anatomage table (AT), a novel 3D anatomical visualization system, we described the nerves passing through the retromastoid area including the great occipital nerve (GON), the lesser occipital nerve (LON) and the great auricular nerve (GAN), and their courses from the origins, till terminal branches. Moreover, using dedicated software, we measured distances between the nerves and well-recognizable bony landmarks. After identifying the nerves and their distances from bony landmarks, we observed that the safest and risk-free skin incision should be made in an area delimited, superiorly from the superior nuchal line (or slightly higher), and inferiorly from a plane passing at 1-1.5 cm above the mastoid tip. The lateral aspect of such an area should not exceed 9.5-10 cm from the inion, while the medial one should be more than 7 cm far from the inion. This anatomical information has been useful in defining anatomical landmarks and reducing the risk of complications, mainly related to nerve injury, in RA. In-depth neuroanatomic knowledge of the cutaneous nerves of the retromastoid area is essential to minimize the complications related to their injury during different neurosurgical approaches. Our findings suggest that the AT is a reliable tool to enhance understanding of the anatomy, and thus contributing to the refinement of surgical techniques.

Primary Intracranial Gliosarcoma: Is It Really a Variant of Glioblastoma? An Update of the Clinical, Radiological, and Biomolecular Characteristics.

Gliosarcomas (GS) are sporadic malignant tumors classified as a Glioblastoma (GBM) variant with IDH-wild type phenotype. It appears as a well-circumscribed lesion with a biphasic, glial, and metaplastic mesenchymal component. The current knowledge about GS comes from the limited literature. Furthermore, recent studies describe peculiar characteristics of GS, such as hypothesizing that it could be a clinical-pathological entity different from GBM. Here, we review radiological, biomolecular, and clinical data to describe the peculiar characteristics of PGS, treatment options, and outcomes in light of the most recent literature. A comprehensive literature review of PubMed and Web of Science databases was conducted for articles written in English focused on gliosarcoma until 2023. We include relevant data from a few case series and only a single meta-analysis. Recent evidence describes peculiar characteristics of PGS, suggesting that it might be a specific clinical-pathological entity different from GBM. This review facilitates our understanding of this rare malignant brain tumor. However, in the future we recommend multi-center studies and large-scale metanalyses to clarify the biomolecular pathways of PGS to develop new specific therapeutic protocols, different from conventional GBM therapy in light of the new therapeutic opportunities.

Semi-automated assessment of the principal diffusion direction in the corpus callosum: differentiation of idiopathic normal pressure hydrocephalus from neurodegenerative diseases.

BACKGROUND: Idiopathic normal pressure hydrocephalus (iNPH) shares clinical and radiological features with progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). Corpus callosum (CC) involvement in these disorders is well established on structural MRI and diffusion tensor imaging (DTI), but alterations overlap and lack specificity to underlying tissue changes. OBJECTIVE: We propose a semi-automated approach to assess CC integrity in iNPH based on the spatial distribution of DTI-derived principal diffusion direction orientation (V1). METHODS: We processed DTI data from 121 subjects (Site1: iNPH = 23, PSP = 27, controls = 14; ADNI: AD = 35, controls = 22) to obtain V1, fractional anisotropy (FA) and mean diffusivity (MD) maps. To increase the estimation accuracy of DTI metrics, analyses were restricted to the midsagittal CC portion (± 6 slices from midsagittal plane). Group-wise comparison of normalized altered voxel count in midsagittal CC was performed using Kruskal-Wallis tests, followed by post hoc comparisons (Bonferroni-corrected p < 0.05). ROC analysis was used to evaluate the diagnostic power of DTI alterations compared to callosal volume. RESULTS: We found specific changes of V1 distribution in CC splenium of iNPH compared to AD and PSP, while MD and FA showed patterns of alterations common to all disorders. ROC curves showed that, compared to splenial volume, V1 represented the most accurate marker of iNPH diagnosis versus AD and PSP. CONCLUSIONS: Our results provide evidence that V1 is a powerful biomarker for distinguishing patients with iNPH from patients with AD or PSP. Indeed, our findings also provide more specific insight into the pathophysiological mechanisms that underlie tissue damage across iNPH and its mimics.

Blink reflex recovery cycle distinguishes patients with idiopathic normal pressure hydrocephalus from elderly subjects.

BACKGROUND: The R2 component of blink reflex recovery cycle (R2BRrc) is a simple neurophysiological tool to detect the brainstem hyperexcitability commonly occurring in several neurological diseases such as Parkinson's disease and atypical parkinsonisms. In our study, we investigated for the first time the usefulness of R2BRrc to assess brainstem excitability in patients with idiopathic Normal Pressure Hydrocephalus (iNPH) in comparison with healthy subjects. METHODS: Eighteen iNPH patients and 25 age-matched control subjects were enrolled. R2BRrc was bilaterally evaluated at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in all participants. We investigated the diagnostic performance of R2BRrc in differentiating iNPH patients from control subjects using ROC analysis. Midbrain area and Magnetic Resonance Hydrocephalic Index (MRHI), an MRI biomarker for the diagnosis of iNPH, were measured on T1-weighted MR images, and correlations between R2BRrc values and MRI measurements were investigated. RESULTS: Fourteen (78%) of 18 iNPH patients showed an enhanced R2BRrc at ISIs 100-150-200 ms, while no control subjects had abnormal R2BRrc. The mean amplitude of bilateral R2BRrc at the shortest ISIs (100-150-200 ms) showed high accuracy in differentiating iNPH patients from controls (AUC = 0.89). R2BRrc values significantly correlated with midbrain area and MRHI values. CONCLUSIONS: This study represents the first evidence of brainstem hyperexcitability in iNPH patients. Given its low cost and wide availability, R2BRrc could be a useful tool for selecting elderly subjects with mild gait and urinary dysfunction who should undergo an extensive diagnostic workup for the diagnosis of NPH.

Spinal Cord Stimulation in Chronic Low Back Pain Syndrome: Mechanisms of Modulation, Technical Features and Clinical Application.

Chronic low-back pain (CLBP) is a common disease with several negative consequences on the quality of life, work and activity ability and increased costs to the health-care system. When pharmacological, psychological, physical and occupational therapies or surgery fail to reduce CLBP, patients may be a candidate for Spinal Cord Stimulation (SCS). SCS consists of the transcutaneous or surgical implantation of different types of electrodes in the epidural space; electrodes are then connected to an Implanted Pulse Generator (IPG) that generates stimulating currents. Through spinal and supraspinal mechanisms based on the "gate control theory for pain transmission", SCS reduces symptoms of CLBP in the almost totality of well-selected patients and its effect lasts up to eight years in around 75% of patients. However, the evidence in favor of SCS still remains weak, mainly due to poor trial methodology and design. This narrative review is mainly addressed to those professionals that may encounter patients with CLBP failing conventional treatments. For this reason, we report the mechanisms of pain relief during SCS, the technical features and some clinical considerations about the application of SCS in patients with CLBP.

Pilocytic Astrocytoma-Derived Cells in Peripheral Blood: A Case Report.

Imaging limitations, invasive tissue biopsies and poor information over the course of treatment to evaluate 'real-time' tumor dynamics justify the emerging use of liquid biopsies in the field of brain tumors. Circulating tumor cells (CTCs) from high-grade astrocytomas might reach the circulation by crossing the blood-brain barrier. Here, for the first time, CTCs cytology in a case of pylocitic astrocytoma is described. An obstructive hydrocephalous due to a lateral mesencephalic tectum mass occluding the Silvio Aqueduct was diagnosed in a young, 18 years old, male. Considering the location of the tumor and the rapid deterioration of the neurological status, it has been decided to urgency treat the patient with ventriculoperitoneal shunting. Magnetic resonance imaging showed a nodular shaped lesion localized within the left lateral mesencephalic tectum. Stereotactic biopsy was not approachable due significant risk of neurological consequences. The diagnosis was performed by blood sampling, a non-invasive procedure for the patient, in order to provide tumor information. Cytopathological features on detected circulating atypical GFAP positive cells led to pilocytic diagnosis confirmed by the patient's 68 months outcome.